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Abstract

Background

Magnolia (Magnolia officinalis) and Phellodendron (Phellodendron amurense) barks are medicinal plants commonly used as traditional remedies for reducing stress
and anxiety. Modern dietary supplements are intended to induce relaxation and reduce
stress as well as stress-related eating. Previous studies have shown the combination
of Magnolia/Phellodendron (MP) to reduce both cortisol exposure and the perception
of stress/anxiety, while improving weight loss in subjects with stress-related eating.
Competitive athletes are “stressed” by their intense exercise regimens in addition
to their normal activities of daily living and thus may benefit from a natural therapy
intended to modulate baseline perceptions of stress and stress hormone exposure.

Methods

We assessed salivary cortisol exposure and psychological mood state in 56 subjects
(35 men and 21 women) screened for moderate stress and supplemented with a standardized/patented
MP combination (Relora®, Next Pharmaceuticals) or Placebo for 4 weeks.

Results

After 4 weeks of supplementation, salivary cortisol exposure was significantly (p<0.05)
lower (−18%) in the Relora group compared to Placebo. Compared to Placebo, the Relora
group had significantly better (p<0.05) mood state parameters, including lower indices
of Overall Stress (−11%), Tension (−13%), Depression (−20%), Anger (−42%), Fatigue
(−31%), and Confusion (−27%), and higher indices of Global Mood State (+11%) and Vigor
(+18%).

Conclusion

These results indicate that daily supplementation with a combination of Magnolia bark
extract and Phellodendron bark extract (Relora®) reduces cortisol exposure and perceived daily stress, while improving a variety
of mood state parameters, including lower fatigue and higher vigor. These results
suggest an effective natural approach to modulating the detrimental health effects
of chronic stress in moderately stressed adults. Future studies should examine the
possible performance and recovery benefits of Relora supplementation in athletes overstressed
by the physical and psychological demands of training and competition.

Keywords:

Stress; Cortisol; Vigor; Magnolia; Phellodendron; Mood; Relora

Background

The relationship between chronic psychological stress and reduced health is well established
[1], with psychological stress having been shown to increase susceptibility to a wide
range of diseases including anxiety, depression, diabetes, and obesity
[2-4]. Even the “stress” of short-term sleep loss has significant implications for long-term
health and well-being due to adverse systemic health effects including suppressed
immune function, abdominal obesity, insomnia, depression, and generalized fatigue
[5,6].

Interventions for stress and anxiety range from nutritional support to the use of
antidepressant medications such as benzodiazepines and selective serotonin reuptake
inhibitors
[7,8]. A United States Patent (No. 6,582,735) has been granted for the use of an extract
of Magnolia officinalis bark for stress related conditions involving elevated cortisol, such as control of
body weight, sleep disturbances and restlessness
[9].

Extracts of Magnolia officinalis bark and its active constituent, honokiol, have been studied in animal models with
comparable anxiolytic activity to diazepam (a benzodiazepine anxiolytic used to treat
anxiety), but without associated side effects such as sedation
[10-13]. Berberine, a constituent of the Phellodendron extract, has also demonstrated a significant anxiolytic effect in rodent stress studies,
including the elevated plus maze test and the forced swim test
[14,15]. The combination of magnolia plus phellodendron appears to be even more effective
in controlling stress/anxiety compared to either herb used separately
[16-19].

The subject of this study, Relora® (Next Pharmaceuticals, Inc, Salinas, CA), is a
proprietary dietary supplement formulation consisting of a blend of extracts of Magnolia officinalis bark and Phellodendron amurense bark standardized to honokiol and berberine, respectively. In previous studies, Relora
has demonstrated efficacy for reducing stress and anxiety in animals
[18,19] and enhancing feelings of well-being in human subjects
[20,21]. One study also measured the effects of Relora on salivary cortisol, finding benefits
in reducing cortisol and increasing dehydroandrostenedione (DHEA) levels in stressed
subjects
[20].

In this study, we report the effects of using the Relora combination of magnolia bark
and phellodendron bark on salivary cortisol and psychological well-being of healthy
subjects under moderate levels of perceived psychological stress. The current study
employed a well-validated psychological assessment known as the Profile of Mood States
(POMS) to assess mood state. A key objective of the study was to explore how 4 weeks
of magnolia/phellodendron supplementation (Relora versus a placebo) affected cortisol,
various moods, and overall stress levels under conditions of moderate psychological
stress.

Methods

Dietary supplement

Relora® is a proprietary blend of a patented extract of the bark of Magnolia officinalis and an extract of the bark of Phellodendron amurense (US Patent Nos. 6,582,735 and 6,814,987). The product is standardized to “not less
than 1.5% honokiol and 0.1% berberine.” Subjects ingested 500 mg/day at breakfast
(250 mg) and dinner (250 mg) in white opaque capsules or a look-alike placebo that
was identical in size, shape and color.

Study design

This study was done in accordance with the Helsinki Declaration, as revised in 1983,
for clinical research involving humans and all procedures, measurements, and informed
consent processes were reviewed and approved by an external third-party review board
(Aspire IRB; Santee, CA).

Subjects signed informed consent documents after the study details were explained.
The study used a randomized placebo-controlled, double-blind design. Subjects were
randomly assigned, through a random number generator, to either 500 mg/day containing
supplement (250 mg of Relora®, consumed at breakfast and dinner) or a look-alike Placebo
(250 mg of rice flour); bottles were labeled only with a pre-assigned random code.
Subjects self-administered the allotted capsule twice daily in the morning with breakfast
and in the evening with dinner for 4 weeks. Subjects were contacted weekly to remind
them to take their capsules daily. Empty bottles were returned after the study for
a count of any unused capsules (an indicator of missed doses). Compliance with these
instructions was high (data not shown).

We screened 60 subjects for moderate levels of psychological stress, with 56 subjects
completing the study. Sixty (60) subjects were randomized to receive Supplement (30
subjects) or look-alike Placebo (30 subjects) for 4 weeks. The 4-week duration was
selected as more representative of persistent changes in mood state that may result
from superior hormone balance, as opposed to short-term changes in emotions that may
be more closely linked with stressors of daily living.

At Baseline (week 0) and Post-supplementation (week 4), we assessed body weight and
body fat percentage (Tanita BDF-300A bioelectrical impedance analyzer), overall stress
(Yale Stress Survey), psychological mood state (Profile of Mood States Survey) and
salivary cortisol. Mood State (Vigor, Depression, Anger, Confusion, Fatigue, and Anxiety)
was assessed using the validated Profile of Mood States (POMS) survey
[22,23]. Cortisol exposure was assessed in pooled saliva samples collected at three time
points during each collection day (morning, afternoon, and evening). The morning sample
was collected upon waking at approximately 6am; the afternoon sample at approximately
2pm; and the evening sample immediately before bed at approximately 10pm to represent
as much of a total daily “cortisol exposure” for each subject as possible. Cortisol
circadian rhythm data will be reported elsewhere. Saliva samples were analyzed for
free cortisol by enzyme immunoassay (EIA; Salimetrics, State College, PA, USA).

Fifty-six subjects (35 men & 21 women, age 28±11 years) completed the study, with
two women in each group lost to follow up (did not return final surveys or saliva
samples).

Mood assessment

We employed the Profile Of Mood States (POMS) questionnaire, to measure 6 primary
psychological factors (tension, depression, anger, fatigue, vigor or confusion), plus
the combined “global mood state” as an indication of subjective well-being. The POMS
methodology has been used in nearly 3,000 studies and its validity is well established.
The POMS profile uses 65 adjective-based intensity scales scored on a 0–4 hedonic
scale (0 = not at all, 4 = extremely). The 65 adjective responses are categorized
into the six mood factors (tension, depression, anger, fatigue, vigor or confusion),
tabulated, scored and analyzed. The output of the POMS questionnaire is an assessment
of the positive and negative moods of each subject at baseline and 4-weeks.

Data management and analysis

All questionnaires were completed at a central location and transcribed to a central
database. Subjects that did not complete the questionnaires or submitted incomplete
questionnaires were dropped from the study and not included in the study analysis
(four subjects – two females from each group). Data was identified by subject number
and examined for accuracy and completeness. Tabulated data was analyzed with JMP 8.0
(SAS Institute) using standard parametric paired t-tests and significance was assessed
with a two-tailed alpha level set at 0.05.

Results

Over the course of the 4-week supplementation period, there were no adverse events
or side effects reported. There were no significant changes in body weight or body
fat percentage.

7.4). The global mood state was calculated based on scoring (0-4 with 0 = not at all,
2 = moderately and 4 = extremely) answers to 58 of the 65 adjectives of the POMS (a
lower number is a “better” global mood state). Global Mood State is the combined score
of the 6 subscales of the POMS (McNair et al.,
[9]).

Figure 3.Profile of Mood States (POMS). Numerical scores for each of the 6 subscales of the POMS (McNair et al.,
[9]). The Relora group showed significantly improved mood state parameters compared to
Placebo at Week 4 (* = p<0,05).

Discussion

Antidepressant drugs are the most commonly prescribed class of medications in the
United States and are used by athletes and non-athletes alike
[24]. More than 10% of the American population is taking one or more antidepressant drugs,
which represents 27 million individuals taking more than 120 million prescriptions
and spending over $80 billion per year. According to a recent survey
[25], large numbers of Americans feel an antidepressant drug would be helpful for; dealing
with day-to-day stresses (83%); making things easier in relations with family and
friends (76%); and helping people feel better about themselves (68%). However, because
antidepressant drugs carry the United States Food and Drug Administration’s most stringent
“black box” warning (associated with serious life-threatening adverse effects), there
is need for safe and effective natural approaches to reducing stress and anxiety.

In addition to a balanced diet, regular physical activity, and various stress management
techniques, certain dietary supplements may be effective in naturally maintaining
the normal balance between stress, cortisol, and emotional well-being. For example,
there are numerous commercial examples of general-purpose “relaxation” and “calming”
teas based on traditional herbal blends such as chamomile, fennel, lemon balm and
others, while magnolia and phellodendron bark extracts have been specifically demonstrated
as natural anxiolytic agents,
[7-21,26]. As such, appropriate dietary supplements may be a safe and effective natural adjunct
to diet/exercise/stress management techniques to bring stress response and cortisol
levels back to within normal ranges in individuals suffering from chronic stress or
in athletes suffering from overtraining syndrome.

Magnolia bark (Magnolia officinalis) and Phellodendron bark (Phellodendron amurense) are traditional herbal medicines used since 100A.D. for treating “stagnation of
Qi” in Chinese medicine
[7,8,17], which is analogous to what we view in Western medicine as reduced psychological
vigor or burnout. Magnolia bark extracts are rich in the phenolic compound, honokiol
[12], while Phellodendron bark extracts are rich in berberine
[14,15] – each of which contributes to the primary anti-stress, anti-anxiety, and cortisol-lowering
effects of the plants
[9-19,26]. Research has shown magnolia and phellodendron extracts and their primary bioactives
(honokiol and berberine) to possess powerful “mental acuity” benefits
[10,11,16] via their actions in modulating the activity of various neurotransmitters and related
enzymes in the brain, including brain-derived neurotrophic factor, acetylcholine,
choline acetyltransferase, and acetylcholinesterase.

Numerous animal studies have demonstrated that honokiol and berberine act as anxiolytic
agents
[9-19,26]. When compared to pharmaceutical agents such as Valium (diazepam), honokiol and berberine
appear to be as effective in their anti-anxiety activity yet not nearly as powerful
in their sedative ability
[9,12,13]. These results have been demonstrated in numerous animal studies and suggest that
Relora, which is standardized to both honokiol (from magnolia bark) and berberine
(from phellodendron), is an effective natural approach for controlling the detrimental
effects of everyday stressors, without the tranquilizing side effects of pharmaceutical
agents
[14-19,26]. Previous human studies on Relora have shown similar anti-stress and anxiolytic benefits
in moderately stressed subjects
[20,21]. The results reported in this study expand on previous findings of simple “relaxation”
benefits of Relora to demonstrate specific effects on psychological mood state parameters
in moderately-stressed subjects, including benefits for Global Mood State (analogous
to an assessment of overall well-being), Tension, Depression, Fatigue, and Vigor (the
opposite psychological state from “Burnout”). The magnitude of benefit in stress hormone
(cortisol) reduction (18%) and mood state improvement (11%-42%) is meaningful from
the perspective of optimal mental and physical performance. For example, the 18% higher
Vigor or the 20% lower Depression score observed in the Relora group, could reasonably
be associated with subjects reporting “feeling good” (in the case on our moderately-stressed
subjects) or “performing well” (in the case of over-stressed or over-trained athletes,
which should be the subject of future studies).

Although our study was not conducted in competitive athletes, a number of our moderately
stressed healthy subjects were recreational runners and cyclists who commented about
feeling more “balanced” in their workouts when their stress levels were balanced.
This is a logical individual perception based on a number of studies in elite-level
and recreational athletes that have found a direct relationship between overall stress
(physical training and psychological stress) and athletic performance, including both
mental and physical performance parameters
[27-31]. Competitive athletes tend to be characterized by an elevated Vigor score and lower
Fatigue score compared to non-athletes
[27]. However, in many intervention studies of athletes, a dose–response exists between
training stress and mood state
[28,29], so as overall physical “training stress” is elevated beyond a certain tipping point,
psychological mood state becomes depressed. In addition, low Vigor scores and overall
reduced psychological mood state have been identified as predictors of future athletic
injury
[30]. The most dramatic changes in psychological mood state are logically the result of
intensified periods of training (e.g. increased training intensity and/or duration),
which can be modulated positively or negatively by psychological stress (e.g. exams),
competitive anxiety, social support network, sleep patterns, and recovery methods
[27-31]. Based on the magnitude of the positive changes in cortisol levels and mood state
parameters, we would recommend further athlete-specific studies to gauge the possible
mental/physical performance benefits of Relora in enhancing post-exercise recovery
and preventing over-training syndrome in competitive athletes.

Results from the current study indicate that daily supplementation with a combination
of magnolia bark and phellodendron bark (Relora) reduces cortisol exposure and perceived
stress, while improving a variety of mood state parameters. Compared to the Placebo
group, salivary cortisol exposure was significantly lower (−18%) in the Relora group,
while mood state parameters were significantly and meaningfully higher, including
an 11% superior Global Mood State and 18% higher Vigor, with 13% lower Tension and
20% lower Depression indices. These results indicate that daily supplementation with
a combination of Magnolia and Phellodendron (Relora) is an effective natural approach
to the detrimental health effects of chronic stress.

Conclusions

The present study indicates a significant “anti-stress” benefit of magnolia/phellodendron
bark (Relora) supplementation in moderately stressed non-athletes, and suggests a
possible benefit for athletes to recover from “training stress” induced by the physical
and psychological demands of competition and training. Future studies should examine
the potential benefits of Relora in helping athletes to enhance post-exercise recovery
and possibly to help prevent overtraining syndrome.

Competing interests

This study was funded by the manufacturer of Relora (Next Pharmaceuticals) and conducted
by SupplementWatch. The authors of this paper have no direct financial relationship
with Next Pharmaceuticals or with the Relora dietary supplement. ST and JT are employees
of SupplementWatch. ST and MP are employees of MonaVie, which markets a dietary supplement
containing Relora as one of several ingredients.

Authors’ contributions

Each author contributed significantly to the successful carriage of this study. ST
designed the study and drafted the manuscript. JT coordinated the IRB approval, subject
visits, and sample inventory. MP participated in the study design and coordination
of subject visits. All authors read and approved the manuscript.